Mini-review: Transcranial Alternating Current Stimulation and the Cerebellum.

Oscillatory activity in the cerebellum and linked networks is an important aspect of neuronal processing and functional implementation of behavior. So far, it was challenging to quantify and study cerebellar oscillatory signatures in human neuroscience due to the constraints of non-invasive cerebellar electrophysiological recording and interventional techniques. The emerging cerebellar transcranial alternating current stimulation technique (CB-tACS) is a promising tool, which may partially overcome this challenge and provides an exciting non-invasive opportunity to better understand cerebellar physiology.Several studies have successfully demonstrated that CB-tACS can modulate the cerebellar outflow and cerebellum-linked behavior. In the present narrative review, we summarize current studies employing the CB-tACS approach and discuss open research questions. Hereby, we aim to provide an overview on this emerging electrophysiological technique and strive to promote future research in the field. CB-tACS will contribute in the further deciphering of cerebellar oscillatory signatures and its role for motor, cognitive, or affective functions. In long term, CB-tACS could develop into a therapeutic tool for retuning disturbed oscillatory activity in cerebellar networks underlying brain disorders.

Ketamine treatment upon memory retrieval reduces fear memory in marmoset monkeys.

Emotionally arousing experiences are retained very well as seen in posttraumatic stress disorder (PTSD). Various lines of evidence indicate that reactivation of these memories renders them labile which offers a potential time-window for intervention. We tested in non-human primates whether ketamine, administered during fear memory reactivation, affected passive (inhibitory) avoidance learning. For the consolidation of contextual emotional memory, the unescapable foot-shock paradigm in a passive avoidance task with two compartments (dark vs illuminated) was used. After entering the dark compartment, marmoset monkeys received four random foot-shocks (1 mA, 4 s) within 15-min. This stressful exposure increased the saliva cortisol and heart rate and impaired REM-sleep (p<0.05). One week later the monkeys were re-exposed to the stressful situation for the reconsolidation of the fearful experience. During the re-exposure the monkeys were treated with ketamine (0.5 mg/kg) or saline. In week 3, the monkeys were placed in the experimental setting to test their memory for the fearful experience. In contrast to the vehicle-treated monkeys, who avoided the dark compartment, the ketamine-treated monkeys entered the dark compartment that was previously associated with the fearful experience (p<0.05). Post-mortem analysis of the hippocampus showed that ketamine-treated animals exhibited less doublecortin positive neurons and BrdU-labeled cells in the dentate gyrus. This study reveals that a single low dose of ketamine, administered upon fear retrieval in monkeys, reduce contextual fear memory and attenuate neurogenesis in the hippocampus. These are important findings for considering ketamine as a potential candidate to target traumatic memories in PTSD.

Neurotechnologies as tools for cognitive rehabilitation in stroke patients.

INTRODUCTION: Cognitive impairments are one of the most common remaining symptoms after a stroke. The use of neurotechnologies to enhance cognitive performance is a rapidly emerging field with encouraging results. AREAS COVERED: Here, the authors empirically review the respective literature and critically discuss the technologies that are currently most often used for cognitive enhancement in stroke patients, which are computerized cognitive training, virtual reality, noninvasive brain stimulation and brain-computer interfaces. The authors describe their advantages/disadvantages and the challenges and limitations to overcome. EXPERT OPINION: Although the current results are promising, more research is needed to be able to make conclusive statements and translate these approaches successfully in daily clinical life. Multidiscipline collaborations could aid to improve current neurotechnologies and provide guidelines for future implementations.

Cerebellar transcranial alternating current stimulation in the gamma range applied during the acquisition of a novel motor skill.

The development of novel strategies to augment motor training success is of great interest for healthy persons and neurological patients. A promising approach is the combination of training with transcranial electric stimulation. However, limited reproducibility and varying effect sizes make further protocol optimization necessary. We tested the effects of a novel cerebellar transcranial alternating current stimulation protocol (tACS) on motor skill learning. Furthermore, we studied underlying mechanisms by means of transcranial magnetic stimulation and analysis of fMRI-based resting-state connectivity. N = 15 young, healthy participants were recruited. 50 Hz tACS was applied to the left cerebellum in a double-blind, sham-controlled, cross-over design concurrently to the acquisition of a novel motor skill. Potential underlying mechanisms were assessed by studying short intracortical inhibition at rest (SICIrest) and in the premovement phase (SICImove), intracortical facilitation at rest (ICFrest), and seed-based resting-state fMRI-based functional connectivity (FC) in a hypothesis-driven motor learning network. Active stimulation did not enhance skill acquisition or retention. Minor effects on striato-parietal FC were present. Linear mixed effects modelling identified SICImove modulation and baseline task performance as the most influential determining factors for predicting training success. Accounting for the identified factors may allow to stratify participants for future training-based interventions.

Non-invasive brain stimulation to enhance cognitive rehabilitation after stroke.

Stroke is a main cause for long-term disability. Stroke symptoms cover various domains, e.g., motor, sensory, language, or other cognitive functions. In clinical practice and rehabilitation research, especially motor impairment attracts much attention. However, also cognitive impairments are common after stroke, effecting approximately two-thirds of stroke patients in the acute phase. Although 30% of stroke patients spontaneously recover from their cognitive impairments, large amounts of patients remain cognitively impaired. These patients have more problems reintegrating in personal and professional life. To date, cognitive rehabilitation strategies are not yet satisfactory. One promising strategy is combining non-invasive brain stimulation (NIBS) with cognitive training. In the current review, we will discuss the relevance of cognitive impairment after stroke and innovative interventional strategies to improve cognition, such as NIBS. Furthermore, we will address the potential of using cognitive training to enhance recovery in other behavioural domains, such as the motor domain.

The Effects of Stimulator, Waveform, and Current Direction on Intracortical Inhibition and Facilitation: A TMS Comparison Study.

Background: Cortical function is dependent on the balance between excitatory and inhibitory influences. In the human motor cortex, surrogates of these interactions can be measured in vivo, non-invasively with double-pulse transcranial magnetic stimulation (TMS). To compare results from data acquired with different available setups and bring data together, it is inevitable to determine whether different TMS setups lead to comparable or differential results. Objective: We assessed and compared short intracortical inhibition (SICI) and intracortical facilitation (ICF) testing four different experimental conditions. Methods: SICI and ICF were studied with different stimulators (Magstim BiStim2 or MagVenture MagPro X100), waveforms (monophasic or biphasic), current directions (anterior-posterior or posterior-anterior) at interstimulus intervals (ISIs) of 1, 3, 10, 15 ms. Results: We were not able to detect differences for SICI and ICF, when comparing the tested conditions, except for 3 ms SICI in which the anterior-posterior current direction led to stronger modulation. Correlation analysis suggested comparability for 3 ms SICI for the Magstim monophasic posterior-anterior condition with both tested MagVenture conditions. Conclusions: 3 ms SICI data sets obtained with two different, commonly used stimulators (Magstim BiStim2 or MagVenture MagPro X100) with conventionally used stimulation parameters are largely comparable. This may allow the combination of data sets in an open science view.

Minimum spanning tree analysis of the human connectome.

One of the challenges of brain network analysis is to directly compare network organization between subjects, irrespective of the number or strength of connections. In this study, we used minimum spanning tree (MST; a unique, acyclic subnetwork with a fixed number of connections) analysis to characterize the human brain network to create an empirical reference network. Such a reference network could be used as a null model of connections that form the backbone structure of the human brain. We analyzed the MST in three diffusion-weighted imaging datasets of healthy adults. The MST of the group mean connectivity matrix was used as the empirical null-model. The MST of individual subjects matched this reference MST for a mean 58%-88% of connections, depending on the analysis pipeline. Hub nodes in the MST matched with previously reported locations of hub regions, including the so-called rich club nodes (a subset of high-degree, highly interconnected nodes). Although most brain network studies have focused primarily on cortical connections, cortical-subcortical connections were consistently present in the MST across subjects. Brain network efficiency was higher when these connections were included in the analysis, suggesting that these tracts may be utilized as the major neural communication routes. Finally, we confirmed that MST characteristics index the effects of brain aging. We conclude that the MST provides an elegant and straightforward approach to analyze structural brain networks, and to test network topological features of individual subjects in comparison to empirical null models.

Structural Brain Network Disturbances in the Psychosis Spectrum.

BACKGROUND: Individuals with subclinical psychotic symptoms provide a unique window on the pathophysiology of psychotic experiences as these individuals are free of confounders such as hospitalization, negative and cognitive symptoms and medication use. Brain network disturbances of white matter connections are thought to play a central role in the pathophysiology of psychosis. Based on the structural network disconnection hypothesis in schizophrenia, we expect less and weaker connections, and altered brain network organization in individuals with clinical and those with subclinical psychotic symptoms. METHODS: We used diffusion tensor imaging to study 35 patients with a psychotic disorder, 35 subjects with subclinical psychotic symptoms, and 36 healthy controls. The structural brain network was analyzed on 3 levels: connection density, white matter microstructure (fractional anisotropy, mean diffusivity, and magnetic transfer ratio), and network organization. Network organization was studied with minimum spanning tree analysis, a method to reconstruct a backbone of structural highways in the brain. RESULTS: Decreased fractional anisotropy and increased mean diffusivity was found in both groups with psychotic symptoms, while their network topology showed decreased overlap with a healthy reference network. Decreased centrality was found in several brain regions, including parietal hubs and language areas, in both groups with psychotic symptoms. Deviation of network characteristics was more apparent in clinical subjects than in subclinical subjects. DISCUSSION: Weaker connections and decreased centrality of parietal hubs characterize the structural brain network in subjects with psychotic symptoms. These differences are more notable in clinical than in subclinical subjects with psychotic experiences.